Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity

ABSTRACT

4-(4-(-Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydor yran-4-carboxylic acid and the corresponding N-hydroxy amide, and derivatives thereof, are useful as therapeutic agents.

FIELD OF THE INVENTION

This invention relates to hydroxamic and carboxylic acid derivatives,and to their use in medicine.

BACKGROUND TO THE INVENTION

Metalloproteinases, including matrix metalloproteinases (MMps), (humanfibroblast) collagenase, gelatinase and TNF convertase (TACE), and theirmodes of action, and also inhibitors thereof and their clinical effects,are described in WO-A-96/11209, WO-A-97/12902 and WO-A-97/19075, thecontents of which are incorporated herein by reference. MMW inhibitorsmay also be useful in the inhibition of other marnmalianmetalloproteinases such as the adamalysin family (or ADAMs) whosemembers include TNF convertase (TACE) and ADAM-10, which can cause therelease of TNFα from cells, and others, which have been demonstrated tobe expressed by human articular cartilage cells and also involved in thedestruction of myelin basic protein, a phenomenon associated withmultiple sclerosis.

Compounds which have the property of inhibiting the action ofmetalloproteinases involved in connective tissue breakdown, such ascollagenases, stromelysins and gelatinases, have been shown to inhibitthe release of TNF both in vitro and in vivo. See Gearing etal (1994),Nature 370:555-557; McGeehan etal (1994), Nature 370:558-561;GB-A-2268934; and WO-A-93/20047. All of these reported inhibitorscontain a hydroxamic acid zinc-binding group, as do theimidazole-substituted compounds disclosed in WO-A-95/23790. Othercompounds that inhibit MMP and/or TNF are described in WO-A-95/13289,WO-A-96/11209, WO-A-96/035687, WO-A-96/035711, WO-A-96/035712 andWO-A-96/035714.

WO-A-99/24399 (published after the priority date claimed in thisApplication) discloses further compounds which are useful inhibitors ofmatrix metalloproteinases and/or TNFα-mediated diseases, includingdegenerative diseases and certain cancers. These compounds arerepresented by formula (I):

wherein

m is 0-2;

X is S(O)₁₂;

Y is OH or NHOH;

CR¹R², inter alia, is a cycloalkyl or heterocycloalkyl ring; and

B—N—B, inter alia, is an optionally-substituted heterocycloalkyl orheterocycloalkenyl ring.

SUMMARY OF THE INVENTION

The present invention relates to specific embodiments of the compoundsclaimed in WO-A-99/24399; see claims 1 and 2. Further, it relates tocompositions and uses, as defined in claims 3-15.

DESCRIPTION OF THE INVENTION

As used in this specification, alone or in combination, the term“C₁₋₆alkyl” refers to straight or branched chain alkyl moiety havingfrom one to six carbon atoms, including for example, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

Salts of compounds of the invention include pharmaceutically-acceptablesalts, for example acid addition salts derived from inorganic or organicacids, such as hydrochlorides, hydrobromides, p-toluenesulphonates,phosphates, sulphates, perchlorates, acetates, trifluoroacetates,propionates, citrates, malonates, succinates, lactates, oxalates,tartrates and benzoates.

Salts may also be formed with bases. Such salts include salts derivedfrom inorganic or organic bases, for example alkali metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylarnine salts.

When the “protected carboxy” group in compounds of the invention is anesterified carboxyl group, it may be a metabolically-labile ester offormula CO₂R⁹ where 4-tert-butylphenyl, 2,2,2-trifluoroethyl,1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl, 2-methyl-l-propionyloxypropyl,2,4,6-trimethylbenzyloxymethyl or pivaloylmethyl group.

Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallization, or by formation of a salt if appropriate or possibleunder the circumstances.

The compounds according to the invention exhibit in vitro inhibitingactivities with respect to the stromelysins, collagenases andgelatinases. Compounds according to the invention may also exhibit invitro inhibition of membrane shedding events known to be mediated bymetalloproteinases, for example, TNF release, TNF receptor shedding,IL-6 receptor shedding, IL-1 receptor shedding, CD23 shedding andL-selectin shedding. The activity and selectivity of the compounds maybe determined by use of the appropriate enzyme inhibition test, forexample as described in WO-A-99/24399. They may be used and formulatedas described in WO-A-099/24399, the contents of which are incorporatedherein by reference.

Intermediate 1 Diethyl Tetrahydropyran-4,4-dicarboxylate

Diethyl malonate (32.0 g) was added to a solution of sodium ethoxide (1equivalent) in ethanol and the solution was stirred for 30 min.2-Bromoethyl ether (46.0 g) was then added and the mixture was stirredat reflux for 3 h. The mixture was then cooled, evaporated in vacuo andthe residue partitioned between water and dichloromethane. The organiclayer was separated and washed with water and brine, then dried (MgSO₄)and evaporated. The residue was then purified by flash columnchromatography on silica gel, eluting with 4:1 hexanes/ether, to givethe title compound (28.0 g) as colourless liquid.

R_(f) 0.33 (4:1 hexanes/ether).

Intermediate 2 Ethyl 4-Hydroxymethyltetrahydropyran-4carboxylate

A solution of di-isobutylaluminium hydride in toluene (82 mmol) wasadded to a solution of intermediate 1 (9.5 g) in toluene at −40° C. over30 min. The mixture was stirred for 1 h, then ethanol (100 ml) was addeddropwise over 30 min. Sodium borohydride (2.0 g) was then added in smallportions over 20 min, and the mixture stirred for 1 h. Saturated sodiumsulfate (100 ml) was then added dropwise followed by ethyl acetate (200ml). The mixture was vigorously stirred for 1 h, then filtered throughCelite and the filtrate evaporated to give the title compound (5.6 g) ascolourless liquid.

R_(f) 0.60 (EtOAc).

Intermediate 3 Ethyl4-(Methanesulfonyloxy)methyltetrahydropyran-4-carboxylateMethanesulfonyl chloride (4.6 ml) was added to a solution ofintermediate 2 (1 1.0 g) at 0° C. in dichloromethane (30 ml), followedby triethylamine (8.0 ml). The mixture was stirred for 1 h, then washedwith citric acid (5% aq, 30 ml), saturated sodium bicarbonate and brine.The organic layer was separated, and then dried (MgSO₄) and evaporatedto give the title compound as colourless oil (15.2 g).

R_(f) 0.65 (ether).

Intermediate 4 Ethyl4-(Acetylsulfanylmethyl)tetrahydropyran-4-carboxylate

A solution of intermediate 3 (16.0 g), sodium iodide (0.2 g) andpotassium thioacetate (12.0 g) in dimethylformamide (100 ml) was heatedat 80° C. for 6 h. The resulting black viscous mixture was then added toaqueous bicarbonate (300 ml) and extracted with ether. The ether layerwas washed with water and brine, then dried (MgSO₄) and evaporated. Theresidue was purified by flash column chromatography on silica gel,eluting with 1:1 ether/hexanes, to give the title compound (6.5 g) aspale yellow oil.

R_(f) 0.45 (1:1 ether/hexanes).

Intermediate 5 Ethyl4-(Chlorosulfonyl)methyltetrahydropyran-4-carbosylate

Chlorine gas was bubbled through a suspension of intermediate 4 (3.2 g)in water (100 ml) and acetic acid (5 ml) at,0° C. for 30 min. The yellowsuspension was stirred at the same temperature for 30 min, thenpartially evaporated under vacuum and the aqueous residue extracted withdichioroinethane (100 ml). The combined organic extracts were washedwith iced-cold water and brine, then dried (MgSO₄) and evaporated togive the title compound (3.3 g) as colourless solid.

R_(f) 0.45 (ether).

EXAMPLE 1

Ethyl4-(4-(4-Chlorophenyl)piperazin-1-yl)suffonylmethyl)-tetrahydropyran-4-carboxylate

4-Chlorophenylpiperazine dihydrochloride (7.3 g) and triethylamine (12ml) were stirred in dichloromethane for 10 min, then the mixture wascooled in ice and a solution of intermediate 5 (6.9 g) indichloromethane was added dropwise over 10 min. The mixture was stirredat 0° C. for 3 h, washed with 2% aq. citric acid, saturated sodiumbicarbonate and brine, dried (MgSO₄) and evaporated and the residuepurified by chromatography (EtOAc) to give the title compound (8.60 g)as a beige solid.

R_(f) 0.29 (ether); MS 430 (M⁺).

EXAMPLE 2

4-(4-(4-Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran4-carboxylicAcid

Lithium hydroxide (6 g) was added to a solution of example 1 (8.6 g) inmethanol (150 ml) and water (100 ml) and the solution was heated underreflux for 4 h. The mixture was cooled to RT, evaporated to half volumeunder reduced pressure and then the solution was washed with ether. Theaqueous phase was acidified with citric acid to pH 5 and extracted withdichloromethane (4 x 100 ml). The solvent was washed with brine, dried(MgSO₄) and evaporated to give the title compound (5.60 g, 70%) as beigesolid.

R_(f) 0.20 (EtOAc); MS 402 (M⁺).

EXAMPPLE 34-(4-(4-Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran-4-carboxylicAcid N-lydroxy Amide Hydrochloride

Oxalyl chloride (4 ml) was added to a suspension of example 2 (5.6 g) indichloromethane (100 ml) at 0° C., followed by dimethylforrnamide (1drop). The mixture was stirred for 1 h, then evaporated in vacuo and theresidue azeotroped with dichloromethane/hexanes (3×100 ml). The crudeproduct was dissolved in dichloromethane (50 ml) and triethylarine (5.80ml) and O-TBDMS hyroxylamine (2.24 g) were added. The mixture wasstirred for 3 h, then washed with water, aqueous sodium bicarbonate andbrine, dried and evaporated. The crude product was dissolved in drydichloromethane (100 ml) and HCI in ether (1M, 50 mn) was addeddropwise. The mixture was vigorously stirred for 30 min, then theproduct collected by filtration and washed with ether (2×100 ml) to givethe title compound (5.0 g) as colourless powder.

R_(f) 0.53 (10% MeOH/dichloromethane 1% NH₄OH); MS 418 (M⁺).

EXAMPLE 44-(4-(4-Chloropheenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran-4-carboxylicAcid N-Hydroxy Amide

The compound of Example 2 (50g) is suspended in tetrahydrofuran (500 ml)and heated to reflux. Oxalyl chloride (1 8.9g) is added in portions. Theresulting mixture is stirred at reflux for at least three hours thencooled to ambient temperature giving a slurry of the acid chloride. Asmall addition of water in THF is added to destroy excess oxalylchloride and the solution is stirred out overnight.

A solution of tetrahydrofuran (100 ml) and 50% aqueous hydroxylamine 50ml) is prepared and cooled to 0.5° C. The slurry of acid chloride intetrahydrofuran is added to the hydroxylamine solution in proportionsmaintaining the temperature at less than 20° C. On completion of theaddition the mixture is stirred at ambient temperature for 1 hour andthen tetrahydrofuran removed by atmospheric distillation. The volume ismaintained by the addition of water (600 ml). The atmospheric removal ofTHF is continued until a head temperature of approximately 70° C. isattained. Heating is stopped and the resulting aqueous suspension cooledslowly to 10-20° C. The mixture is adjusted to pH 7.5-8.5 by theaddition of dilute aqueous ammonia and stirred overnight. The product isisolated by filtration. The cake is washed with water (400 ml) and driedat 35-45° C. to give the title compound (45g, 87%) as a white tooff-white solid.

What is claimed is:
 1. A compound,4-(4-(4-Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran-4-carboxylicacid N-hydroxy amide or a salt, solvate, hydrate, N-oxide, protectedamino, or protected hydroxamic acid derivative thereof.
 2. A compound,4(4(4-Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran-4-carboxylicacid or a salt, solvate, hydrate, N-oxide, protected amino or protectedcarboxy derivative thereof.
 3. A compound,4-(4-(4-Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran-4-carboxylicacid N-hydroxy amide hydrochloride or a solvate, hydrate, N-oxide,protected amino, or protected hydroamic acid derivative thereof.
 4. Apharmaceutical composition for use in therapy comprising a compound anda phannaceutically-acceptable diluent or carrier, wherein said compoundis4-(4-(4Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran-4-carboxylicacid N-hydroxy amide or a salt, solvate, hydrate, N-oxide, protectedamino, or protected hydroxamic acid derivative thereof.
 5. Apharmaceutical composition for use in therapy comprising a compound anda pharmaceutically-acceptable diluent or carrier, wherein said compoundis4-(4-(4Chlorophenyl)piperazin-1-yl)sulfonylmethyl)-tetrahydropyran-4-carboxylicacid or a salt, solvate, hydrate, N-oxide, protected amino or protectedcarboxy derivative thereof.